Human Molecular Genetics Advance Access published online on July 21, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh220
© 2004 by Oxford University Press
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1 Georg-August-Universität Göttingen, Abt. Biochemie II, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany
* To whom correspondence should be addressed. E-mail: kfigura{at}gwdg.de.
Article
Efficacy of enzyme replacement therapy in
-mannosidosis mice. A preclinical animal study
2 Anatomisches Institut, University Kiel, Otto-Hahn-Platz 8, 24043 Kiel, Germany
3 Dipartimento di Medicina Interna, Università degli Studi di Perugia, Via del Giochetto, 06126 Perugia, Italy
4 Hemebiotech A/S, Roskildevej 12C, 3400 Hillerød, Denmark
5 Department of Medical Biochemistry IMB, University of Tromsø, N 9037 Tromsø, Norway
6 Christian-Albrecht-Universität, Institut für Biochemie, Olshausenstr. 40, 24098 Kiel, Germany
Abstract 
-Mannosidosis is a lysosomal storage disorder wich manifests itselfs in the excessive storage of mannose-containing oligosaccharides in the lysosomes of multiple peripheral tissues and in the brain. Here we report on the correction of storage in a mouse model of -mannosidosis after intravenous administration of lysosomal acid -mannosidase (LAMAN) from bovine kidney, and human and mouse recombinant LAMAN. The bovine and the human enzyme were barely phosphorylated, while the bulk of the mouse LAMAN contained mannose 6-phosphate recognition markers. The clearance decreased from bovine to human to mouse LAMAN with plasma half times of 4, 8 and 12 min, respectively. The apparent half life of the internalised enzyme was dependent on the enzyme source as well as tissue type and varied between 3 to 16 h. The corrective effect on the storage of neutral oligosaccharides was time-, tissue-, dose-dependent, and the effects were observed to be transient. After a single dose of LAMAN the maximum corrective effect was observed between 2 and 6 days after injection. In general the corrective effect of the human LAMAN was higher than that of the mouse LAMAN and lowest for bovine LAMAN. Injection of 250 mU human LAMAN/g body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney and heart from neutral oligosaccharides. Surprisingly a decrease in mannose containing oligosaccharides was also observed in the brain, with storage levels reported at less than 30% than that found in controls. These data clearly underline the efficacy of enzyme replacement therapy for the correction of storage in -mannosidosis and suggest that this treatment can substantially decrease storage in the brain.
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